Over the years, there have been reports that many common cancers have shown resistance or refractory phenomenon to curative therapies. Some cancers do not respond or respond initially but shortly thereafter, they become resistant to the therapies. Other cancers fail to respond to therapies which include subsequent rounds of treatment after earlier successful rounds of treatment. In other cases, cancers recur several years after completing effective treatment. If the resistance or refractory phenomenon to chemotherapy, radiation therapy or other cancer therapies could be prevented or overcome, it would be a great advance in medicine.
Various anti-cancer agents have been developed in efforts to treat cancers. Many of those potential anti-cancer agents have unfortunately shown drug resistance through a variety of mechanisms. Some tumors do not respond to certain types of anti-cancer agents after initial short therapeutic responses are shown. In some cases, tumor shrinkage reverses and tumors start to grow again in spite of the cancer initially responding to anti-cancer agents.
One potent anti-cancer agent is camptothecin. Camptothecin and related analogs are known as DNA topoisomerase I inhibitors. Irinotecan (CPT-11, Camptosar®) is a currently marketed DNA topoisomerase I inhibitor with some anticancer activity. Although not currently marketed, an active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin, is thought to also have some anticancer activity. Like other anticancer agents, drug resistance has been observed with the use of camptothecin and camptothecin derivatives. For example, resistance to 9-amino or 9-nitro substituted camptothecins has been reported in common cancers. See U.S. Pat. No. 6,194,579.
Various proposals have been made to overcome drug resistance or refractory phenomenon associated with anti-cancer agents. One early attempt to overcome the barrier associated with camptothecin or camptothecin analogs was directed to developing less toxic CPT derivatives. Other attempts include uses of potential drug resistance blockers such as an epidermal growth factor receptor antagonist and Na+/K+ ATPase inhibitors. See US Patent Publication Nos. 2002/0012663 and 2006/0135468.
In spite of the attempts and advances, there continues to be a need to provide a method of treating a resistant or refractory cancer. The present invention addresses this need.